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At least 1,207 records · Page 67Linked to original sources
PubMed2000

A conformational study of the xyloglucan oligomer, XXXG, by NMR spectroscopy and molecular modeling.

A structural study of the XXXG xyloglucan heptasaccharide (X = alpha-D-Xylp(1 --> 6)-beta-D-Glcp and G = beta-D-Glcp) isolated from apple fruit has been undertaken with nmr and molecular mechanics methods. Quantitative 400 MHz nmr data including nuclear Overhauser effect spectroscopy (NOESY) volumes were recorded at both 6 and 20 degrees C. In spite of severe overlapping of resonances, it was possible to estimate summed NOEs for the majority of the anomeric and glucosyl methylene protons. An ensemble-average population of preferred geometries has been established with the CICADA conformational searching algorithm associated with the MM3 force field. Comparison of the theoretical data obtained by back-calculation of the NOESY volumes from the ensemble-average distance matrix program and motional models based on the Stokes-Einstein-Debye relation satisfactorily reproduce the experimental data. Conformational averaging about the mainchain glycosidic linkages includes both the syn and anti conformers and a minor gauche-gauche population is highly probable. The theoretical data overestimate the syn preference of the Glc(c) --> Glc(b) linkage as well as the Glc(c) GT rotamer population. Finally, both the motional models and the conformational search indicate a fairly rigid backbone and greater flexiblity for the xylose side chains.

Carbohydrate Conformation↗
PubMed2000

Bimolecular reaction simulation using Weighted Ensemble Brownian dynamics and the University of Houston Brownian Dynamics program.

We discuss here the implementation of the Weighted Ensemble Brownian (WEB) dynamics algorithm of Huber and Kim in the University of Houston Brownian Dynamics (UHBD) suite of programs and its application to bimolecular association problems. WEB dynamics is a biased Brownian dynamics (BD) algorithm that is more efficient than the standard Northrup-Allison-McCammon (NAM) method in cases where reaction events are infrequent because of intervening free energy barriers. Test cases reported here include the Smoluchowski rate for association of spheres, the association of the enzyme copper-zinc superoxide dismutase with superoxide anion, and the binding of the superpotent sweetener N-(p-cyanophenyl)-N'-(diphenylmethyl)-guanidinium acetic acid to a monoclonal antibody fragment, NC6.8. Our results show that the WEB dynamics algorithm is a superior simulation method for enzyme-substrate reaction encounters with large free energy barriers.

Acetates↗
PubMed2002

Combinatorial protein design.

Combinatorial protein libraries permit the examination of a wide range of sequences. Such methods are being used for denovo design and to investigate the determinants of protein folding. The exponentially large number of possible sequences, however, necessitates restrictions on the diversity of sequences in a combinatorial library. Recently, progress has been made in developing theoretical tools to bias and characterize the ensemble of sequences that fold into a given structure - tools that can be applied to the design and interpretation of combinatorial experiments.

Amino Acids↗
PubMed2001

Reorientational eigenmode dynamics: a combined MD/NMR relaxation analysis method for flexible parts in globular proteins.

An approach is presented for the interpretation of heteronuclear NMR spin relaxation data in mobile protein parts in terms of reorientational eigenmode dynamics. The method is based on the covariance matrix of the spatial functions of the nuclear spin interactions that cause relaxation expressed as spherical harmonics of rank 2. The approach was applied to characterize the dynamics of a loop region of ubiquitin. The covariance matrix was determined from a conformational ensemble generated by a 5 ns molecular dynamics simulation. It was found that the time correlation functions of the dominant eigenmodes decay in good approximation with a single correlation time. From the reorientational eigenmodes, their eigenvalues, and correlation times, NMR relaxation data were calculated in accordance with Bloch-Wangsness-Redfield relaxation theory and directly compared with experimental (15)N relaxation parameters. Using a fitting procedure, agreement between calculated and experimental data was improved significantly by adjusting eigenvalues and correlation times of the dominant modes. The presented procedure provides detailed information on correlated reorientational dynamics of flexible parts in globular proteins. The covariance matrix was linked to the covariance matrix of backbone dihedral angle fluctuations, allowing one to study the motional behavior of these degrees of freedom on nano- and subnanosecond time scales.

Models, Molecular↗
PubMed2001

Improved prediction of the number of residue contacts in proteins by recurrent neural networks.

Knowing the number of residue contacts in a protein is crucial for deriving constraints useful in modeling protein folding, protein structure, and/or scoring remote homology searches. Here we use an ensemble of bi-directional recurrent neural network architectures and evolutionary information to improve the state-of-the-art in contact prediction using a large corpus of curated data. The ensemble is used to discriminate between two different states of residue contacts, characterized by a contact number higher or lower than the average value of the residue distribution. The ensemble achieves performances ranging from 70.1% to 73.1% depending on the radius adopted to discriminate contacts (6Ato 12A). These performances represent gains of 15% to 20% over the base line statistical predictors always assigning an aminoacid to the most numerous state, 3% to 7% better than any previous method. Combination of different radius predictors further improves the performance. SERVER: http://promoter.ics.uci.edu/BRNN-PRED/.

Amino Acid Sequence↗
PubMed2004

ASmodeler: gene modeling of alternative splicing from genomic alignment of mRNA, EST and protein sequences.

Alternative splicing is in important mechanism of modulating gene function and expression which greatly expands transcriptome diversity. ASmodeler is a novel web-based utility that finds gene models including alternative splicing events from genomic alignment of mRNA, EST and protein sequences. User-supplied sequences are aligned against the genome map using the BLAT and SIM4 programs. Resulting exon connectivity is analyzed by applying graph-theoretic methods to build all possible gene models including splice variants. The algorithm essentially combines the genome-based sequence clustering and transcript assembly procedures in a coherent fashion. In addition to the user-supplied sequences, UniGene clusters and many well-known gene predictions such as Genscan, Ensembl and Acembly may be included in gene modeling. The current implementation supports human, mouse and rat genomes. ASmodeler is available at http://genome.ewha.ac.kr/ECgene/ASmodeler/.

Algorithms↗
PubMed2003

Monte Carlo sampling of negative-temperature plasma states.

A Monte Carlo procedure is used to generate N-particle configurations compatible with two-temperature canonical equilibria in two dimensions, with particular attention to nonlinear plasma gyrokinetics. An unusual feature of the problem is the importance of a nontrivial probability density function P0(phi), the probability of realizing a set phi of Fourier amplitudes associated with an ensemble of uniformly distributed, independent particles. This quantity arises because the equilibrium distribution is specified in terms of phi, whereas the sampling procedure naturally produces particle states Gamma; phi and Gamma are related via a gyrokinetic Poisson equation, highly nonlinear in its dependence on Gamma. Expansion and asymptotic methods are used to calculate P0(phi) analytically; excellent agreement is found between the large-N asymptotic result and a direct numerical calculation. The algorithm is tested by successfully generating a variety of states of both positive and negative temperature, including ones in which either the longest- or shortest-wavelength modes are excited to relatively large amplitudes.

Journal Article↗
PubMed2006

Population patch clamp improves data consistency and success rates in the measurement of ionic currents.

Present whole-cell patch-clamp methodology has only moderate consistency and throughput, rendering impractical functional measurements on large numbers of ion channel ligands or on large numbers of unknown or mutant channel genes. In the population patch clamp (PPC) described herein, a single voltage-clamp amplifier sums the whole-cell currents from multiple cells at once, each sealed to a separate aperture in a planar substrate well. The resulting ensemble currents are more consistent from well to well, and the success rate for each recording attempt is >95%. The PPC was implemented by modifying the PatchPlate substrate and amplifiers in the IonWorks patch-clamp instrument. The increased data consistency and likelihood of a successful recording in each well, combined with 384-well measurements in parallel, allow the direct electrophysiological recording of thousands of ensemble ionic currents per day. Therapeutic groups in drug discovery programs require this order of throughput to screen directed compound libraries against ion channel targets. The potential for studying the function of large numbers of ion channel mutants may be realized with the technique. The procedure incorporates subtraction methods that correct for expected distortions and also reliably produces data that agree with previous patch-clamp studies.

4-Aminopyridine↗
PubMed2003

Muscle activity in pilots with and without pressure breathing during acceleration.

BACKGROUND: Fighter pilots are frequently exposed to high acceleration (+Gz) forces during sorties. To counter these forces the pilots wear anti-G ensembles, use positive pressure breathing for G protection (PBG), and perform anti-G straining maneuvers (AGSMs). The purpose of this study was to analyze the muscle activity during sustained high G when no positive pressure breathing was used (control) compared with that during the use of PBG. METHOD: Seven Swedish Air Force fighter pilots volunteered to be exposed to gradual and rapid onset runs to +9 Gz with and without PBG in a human centrifuge. Surface electromyography was recorded from the intercostals, rectus abdominis, vastus lateralis, biceps femoris, and gastrocnemius lateralis. Measured variables included mean muscle activity, relative time with high muscle activity levels, and individual activation preferences. RESULTS: G duration tolerance was significantly longer (p = 0.028) when PBG was used (57 s) compared with control (32 s) during rapid onset runs. The vastus lateralis and the gastrocnemius lateralis generated activity > 50% of a reference contraction for a longer relative time during control (5.8% and 33.6%, respectively) than during PBG (0.3% and 12.7%, respectively). Cumulative muscle activity during acceleration was compared between trials and indicated that some pilots preferred contracting their leg muscles and others their abdominal muscles. CONCLUSION: G duration tolerance time increased when PBG was used during rapid onset sustained exposures. Less relative time with high muscle activity was seen during the use of PBG in two groups of leg muscles. The pilots seemed to have individual muscle activation sequence preferences while performing the AGSMs.

Acceleration↗
PubMed2005

Genomic organization of zebrafish cone-rod homeobox gene and exclusion as a candidate gene for retinal degeneration in niezerka and mikre oko.

PURPOSE: To determine the genomic organization of the zebrafish crx gene and to evaluate if mutations in crx are responsible for the retinal degeneration phenotype in the zebrafish (Danio rerio) mutants niezerka (nie(m743)) and mikre oko (mok(m632)). METHODS: Overlapping fragments were PCR amplified from genomic DNA isolated from homozygous mutant embryos and wild-type siblings (sibs). Amplicons were sequenced and sequence data assembled into contigs. Genomic organization was determined by alignment of contigs with published cDNA sequences and zebrafish genomic sequence from Sanger and Ensembl databases. Linkage analysis used DNA from mapping panels of single homozygous mutant animals with mixed genetic backgrounds. RESULTS: The analysis indicated that the zebrafish crx gene consisted of three exons and 2 introns, and spans 3.8 kb of genomic DNA. The splice junctions were all located within the coding region. Highly repetitive sequences present in non-coding regions of crx and extended tetra-nucleotide repeats in intronic regions were associated with sequence variation between different strains. Homozygous mok(m632) or nie(m743) mutants and their respective wild-type sibs, showed identical patterns of heterozygosity and sequence variations within each line. No mutation in crx were identified in homozygous mok(m632) or nie(m743). Consistent with the absence of identified mutations, linkage analysis excluded linkage of the mutant phenotypes to crx. CONCLUSIONS: Despite the presence of sequence variations in their respective genetic backgrounds, within each line the sequence of crx was identical. Consistent with the absence of mutations, further analysis excluded linkage of the mutant phenotypes to crx. Analysis is in progress to map these loci and identify the genes responsible for the retinal degeneration phenotype in these mutant lines.

Animals↗
PubMed2006

Complementarity of ensemble and single-molecule measures of protein motion: a relaxation dispersion NMR study of an enzyme complex.

Single-molecule fluorescence experiments have shown that the conformation of the complex between Escherichia coli general NAD(P)H:flavin oxidoreductase (FRE) and flavin adenine dinucleotide (FAD) fluctuates over a range of timescales between 10(-4) and 1 s. Here we use (15)N and (13)C relaxation dispersion NMR methods to study millisecond-timescale dynamics in the complex. In this time regime, the protein is extremely flexible, with residues that undergo conformational exchange located throughout the molecule. Three distinct regions of dynamics are quantified, with two of them involving residues making contact to the donor (Tyr-35) and acceptor (FAD) sites that participate in the electron transfer reaction monitored in single-molecule experiments. Modulation of the donor-acceptor distance through these conformational exchange processes, occurring with rates of approximately 400 and 1,200 s(-1) (22 degrees C), affects the rate of electron transfer and partially accounts for the range of the observed dynamics monitored in the fluorescence experiments.

Biochemistry↗
PubMed1988

Brownian dynamics simulation of protein association.

The Brownian Dynamics (BD) method is applied to study the diffusive dynamics and interaction of two proteins, cytochrome c (CYTC) and cytochrome c peroxidase (CYP). We examine the role of protein electrostatic charge distribution in the facilitation of protein-protein docking prior to the electron transfer step, assessing the influence of individual charged amino acid residues. Accurate interaction potentials are computed by iterating the linearized Poisson-Boltzmann (PB) equation around the larger protein CYP. The low dielectric constant inside proteins, electrolyte screening effects and irregular protein surface topography are taken into account. We observe a large ensemble of electrostatically stable encounter complexes seemingly with acceptable geometric requirements for electron transfer rather than a single dominant complex. Stabilities of the large variety of docking complexes are rationalized in terms of generalized charged residue complementarities. However, it is found that the electrostatic interactions giving rise to complex stabilities are somewhat nonspecific in nature. A large series of additional simulations are performed in which individual charged residues on CYTC have been chemically modified. Resulting perturbations of the association rate are significant and qualitatively similar to results observed in comparable kinetics experiments. We therefore demonstrate the potential of the Brownian dynamics method to estimate the effects of site-directed mutagenesis on protein-protein and protein-ligand diffusional association rates.

Amino Acids↗
PubMed2006

A penalty of using anonymous dominant markers (AFLPs, ISSRs, and RAPDs) for phylogenetic inference.

AFLPs (and to a lesser extent ISSRs and RAPDs) are increasingly being used for phylogenetic inference among closely related species. Presence/absence characters for each AFLP allele treat all absences as homologous to one another. With three or more alleles, terminals are grouped by their shared absence of alleles in character-based phylogenetic-inference methods in a manner that is not redundant with their shared presence of an alternative allele. We conducted simulations to quantify how severe the negative effect of using presence/absence characters of individual bands is for phylogenetic inference relative to standard multistate characters. We examined alternative tree topologies, relative branch lengths, numbers of characters, rates of evolution, and numbers of alternative alleles, using both parsimony and Nei-and-Li distance analyses. Multistate parsimony generally outperformed presence/absence parsimony, which in turn outperformed Nei-and-Li distance. Increasing the character-state space (i.e., the number of alternative character states available) was found to be advantageous for all three methods of analysis examined, but was most advantageous for multistate parsimony. However, the advantage of multistate parsimony relative to Nei-and-Li distance decreased when applied to more divergent characters. More parsimony-informative variation generally alleviated the problem associated with scoring multistate characters as presence/absence characters. The ensemble consistency index was lower for presence/absence characters relative to multistate characters.

Computer Simulation↗
PubMed2006

Expressions for the stress and elasticity tensors for angle-dependent potentials.

The stress and elasticity tensors for interatomic potentials that depend explicitly on bond bending and dihedral angles are derived by taking strain derivatives of the free energy. The resulting expressions can be used in Monte Carlo and molecular dynamics simulations in the canonical and microcanonical ensembles. These expressions are particularly useful at low temperatures where it is difficult to obtain results using the fluctuation formula of Parrinello and Rahman [J. Chem. Phys. 76, 2662 (1982)]. Local elastic constants within heterogeneous and composite materials can also be calculated as a function of temperature using this method. As an example, the stress and elasticity tensors are derived for the second-generation reactive empirical bond-order potential. This potential energy function was used because it has been used extensively in computer simulations of hydrocarbon materials, including carbon nanotubes, and because it is one of the few potential energy functions that can model chemical reactions. To validate the accuracy of the derived expressions, the elastic constants for diamond and graphite and the Young's Modulus of a (10,10) single-wall carbon nanotube are all calculated at T = 0 K using this potential and compared with previously published data and results obtained using other potentials.

Journal Article↗
PubMed1993

ENVIRON: a software package to compare protein three-dimensional structures with homologous sequences using local structural motifs.

This work presents a method to compare local clusters of interacting residues as observed in a known three-dimensional protein structure with corresponding clusters inferred from homologous protein sequences, assuming conserved protein folding. For this purpose the local environment of a selected residue in a known protein structure is defined as the ensemble of amino acids in contact with it in the folded state. Using a multiple sequence alignment to identify corresponding residues in homologous proteins, a detailed comparison can be performed between the local environment of a selected amino acid in the template protein structure and the expected local environments at the sets of equivalent residues, derived from the aligned protein sequences. The comparison makes it possible to detect conserved local features such as hydrogen bonding or complementarity in residue substitution. A global measure of environmental similarity is also defined, to search for conserved amino acid clusters subject to functional or structural constraints. The proposed approach is useful for investigating protein function as well as for site-directed mutagenesis experiments, where appropriate amino acid substitutions can be suggested by observing naturally occurring protein variants.

Algorithms↗
PubMed2004

Harmonic oscillators in the Nosé-Hoover environment.

We study the dynamics of an ensemble of noninteracting harmonic oscillators in a nonlinear dissipative environment described by the Nosé-Hoover model, and find the histogram for energy regions of phase space against visiting time by employing numerical simulation. The results agree with the analysis of the Nosé-Hoover equations effected with the method of averaging for small values of the dissipative parameter alpha of the thermostat. We find oscillations at frequencies proportional to sqrt[alpha/m ], m being the characteristic mass of the particle, about the stationary state corresponding to equilibrium, for sufficiently small alpha . In this region of alpha the histogram does not correspond to Gibbs' canonical distribution. For larger values of alpha the motion becomes irregular. The phenomena could have an important bearing upon simulating molecular dynamics in the Nosé-Hoover thermostat.

Journal Article↗
PubMed2006

Understanding the neural correlates of visual perception: a survey of our toolbox.

One of the central goals of neuroscience is to elucidate the link between behavior and neuronal activity at both single neuron level and the level of neuronal ensembles. New analytical approaches and techniques constantly emerge that correlate neural activity with perception and behavior with ever finer temporal and spatial scales. In this article I review some of these approaches employed in studies of visual perception in which perceptual reports were required from subjects. I divide these methods into 'correlational' methods and 'perturbation' methods; the former measures normal neural activity and correlates it with behavior, the latter perturbs normal neural activity to cause behavioral alterations. I compare such approaches applied to primates with those applied to human subjects, and discuss how these approaches could be combined and made more powerful in the future.

Algorithms↗
PubMed2001

A general method for the quantitative analysis of functional chimeras: applications from site-directed mutagenesis and macromolecular association.

Two new parameters, I: and C:, are introduced for the quantitative evaluation of functional chimeras: I: (impact) and C: (context dependence) are the free energy difference and sum, respectively, of the effects on a given property measured in forward and retro chimeras. The forward chimera is made by substitution of a part "a" from ensemble A into the analogous position of homologous ensemble B (S:(B --> A)). The C: value is a measure of the interaction of the interrogated position with its surroundings, whereas I: is an expression of the quantitative importance of the probed position. Both I: and C: vary with the evaluated property, for example, kinetics, binding, thermostability, and so forth. The retro chimera is the reverse substitution of the analogous part "b" from B into A, S:(A --> B). The I: and C: values derived from original data for forward and retro mutations in aspartate and tyrosine aminotransferase, from literature data for quasi domain exchange in oncomodulin and for the interaction of Tat with bovine and human TAR are evaluated. The most salient derived conclusions are, first, that Thr 109 (AATase) or Ser 109 (TATase) is an important discriminator for dicarboxylic acid selectivity by these two enzymes (I: < -2.9 kcal/mol). The T109S mutation in AATase produces a nearly equal and opposite effect to S109T in TATase (C: < 0.4 kcal/mol). Second, an I: value of 5.5 kcal/mol describes the effects of mirror mutations D94S (site 1) and S55D (site 2) in the Ca(2+) binding sites of oncomodulin on Ca(2+) affinity. The second mirror set, G98D (site 1) and D59G (site 2), yields a smaller impact (I: = -3.4 kcal/mol) on Ca(2+) binding; however, the effect is significantly more nearly context independent (C: = -0.6 versus C: = -2.7 kcal/mol). Third, the stem and loop regions of HIV and BIV TAR are predominantly responsible for the species specific interaction with BIV Tat(65-81) (I: = -1.5 to -1.6 kcal/mol), whereas I: = 0.1 kcal/mol for bulge TAR chimeras. The C: values are from -0.3 to -1.2 kcal/mol. The analysis described should have important applications to protein design.

Aspartate Aminotransferases↗